It is known that compounds which are members of the saturated fatty acid N-acylethanolamine (NAE) family have a marked anti-inflammatory activity in animal models of neurological diseases.
PEA has been shown to inhibit peripheral inflammation and mast cell degranulation and to exert antinociceptive effects in rats and mice (Calignano et al., Nature, 1998, 394, 277-281).
In addition to the pharmacological activities shown in animal models, PEA has been reported to attenuate skin inflammation in humans (Kemeny et al.; Skin Pharmacology and Physiology, 2007, 20, 155-161). PEA activates the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR-α), which modulates in turn the activity of pro-inflammatory regulators such as NF-Kb (D'Agostino G. et al., Eur. J. Pharmacol. 2009, 613, 54-9).
Sustaining PEA signalling at the PPAR-α by protecting PEA from degradation is therefore envisaged as a viable approach for the treatment of inflammatory and pain states.
PEA is a preferred substrate for N-acylethanolamine-hydrolysing acid amidase (NAAA), an enzyme that catalytically hydrolyses the NAE to ethanolamine and the corresponding fatty acid. Therefore, inhibition of NAAA is expected to decrease the inactivation of PEA and restore the levels of PEA in pathological conditions characterised by markedly reduced concentration of this signalling molecule.
Methods of treating pain and inflammation by using compounds which act as inhibitors of NAAA have been disclosed e.g. in WO2009/049238 and US 2013/0281490.
The previously reported studies support the notion that inhibition of NAAA can produce therapeutically useful effects and therefore the identification of new and potent NAAA inhibitors is needed in order to provide new therapeutical agents for the treatment of pain and inflammation.